Protection of Zinc against Tumor Necrosis Factor Induced Lethal Inflammation Depends on Heat Shock Protein 70 and Allows Safe Antitumor Therapy

Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
Cancer Research (Impact Factor: 9.33). 09/2007; 67(15):7301-7. DOI: 10.1158/0008-5472.CAN-06-4010
Source: PubMed


Tumor necrosis factor (TNF)-induced inflammation prevents its broad application as an antitumor agent. We here report that addition of ZnSO(4) to the drinking water of mice induces expression of heat shock protein 70 (HSP70) in several organs, notably the gastrointestinal track. Zinc conferred dose-responsive protection against TNF-induced hypothermia, systemic induction of interleukin-6 and NO(x), as well as against TNF-induced bowel cell death and death of the organism. The protective effect of zinc was completely absent in mice deficient in the major HSP70-inducible gene, hsp70.1, whereas transgenic mice constitutively expressing the human HSP70.A gene, under control of a beta-actin promoter, was also protected against TNF, indicating that an increase in HSP70 is necessary and sufficient to confer protection. The therapeutic potential of the protection induced by ZnSO(4) was clearly shown in a TNF/IFNgamma-based antitumor therapy using three different tumor models. In hsp70.1 wild-type mice, but not in hsp70.1-deficient mice, zinc very significantly protected against lethality but left the antitumor effect intact. We conclude that zinc protects against TNF in a HSP70-dependent way and that protection by zinc could be helpful in developing a safer anticancer therapy with TNF/IFNgamma.

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Available from: Philippe Van Lint, May 04, 2015
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    • "Some lines of evidence show the implication of the zinc deficiency in promoting inflammation (Wessels et al. 2013; Giacconi et al. 2012; Biaggio et al. 2010), whereas an adequate intracellular zinc ion bioavailability downregulates TNF-a and IL-1b production (Prasad et al. 2011). Moreover, zinc treatment in ''in vitro'' and ''in vivo'' models upregulates Hsp70 gene expression with a role of protection against inflammation induced by LPS or TNF-a (Van Molle et al. 2007; Krones et al. 2005) . The low-grade of systemic inflammation, generally accomplished by zinc deficiency and altered zincbound Metallothioneins (MT) production (Mocchegiani et al. 2012), is a common condition during ageing. "
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    • "However, PZ did not enhance LPS-mediated HSP70 protein expression in the mouse lung. Van Molle et al. revealed that zinc induced HSP70 expression in mice, particularly in the liver and small intestine, but HSP70 expression in the lung remained rather low [43]. They explained that this is a more specific expression pattern compared with whole-body heat shock, which also induced HSP70 in other organs such as colon and lung. "
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